Immunosuppressive agents are indispensable to inhibit rejection reaction mainly encountered in organ transplantations. Before 1980, no agent was known which can be called a real immunosuppressive agent. Therefore, even in the transplantation of pancreas which is thought to be the easiest one, the rate of success was only 7%. In 1980, cyclosporine A was discovered and the rate of success of organ transplantations was drastically promoted and the era of real organ transplantations initiated. However, cyclosporine A has a very strong toxicity to kidney, so that it is now tried to reduce the amount of cyclosporine A to be used as small as possible by co-employing other drugs. In 1984, FK-506 was discovered from a ray fungus. It was said that this compound has an immunosuppressive effect as high as 10 to 100 times higher than that of cyclosporine A, and at first, side effects such as toxicity to kidney are small (Science, January, 62, 1989). Recently, however, it was confirmed that FK-506 has stronger toxicity to kidney than cyclosporine A and also has a strong toxicity to liver. Thus, an effective immunosuppressive agent with low toxicity, which replaces these compounds is demanded.
In general, among the administration routes of drugs, oral administration is best preferred because it can be carried out in the absence of a doctor and patients can take the drug at their homes. However, the effectiveness of cyclosporine A when orally administered is insufficient.
On the other hand, through studies of action mechanism of analgesics such as morphine, it was found that there are sites called opioid receptors in various organs such as brain, to which these substances are specifically bound. The compounds which are bound to the receptors and exhibit pharmacological effects such as analgesic effect are called agonists.
The compounds which have affinities to the abovementioned opioid receptors but do not exhibits opioid activities, which exhibit antagonistic effects to opioid compounds are called opioid antagonists. Known opioid antagonists, such as naloxone and naltrexone, are used for studies of analgesic effects of the agonists such as morphine, and for treatment of respiration inhibition which is a side effect caused by administration of opiates such as morphine.
It was recently found that there are three subtypes called .mu., .kappa. and .delta. in opioid receptors. To study each of the subtypes, ligands, that is, agonists and antagonists which are specifically bound to eachsubtype are sought. It was recently confirmed that among these subtypes, the one which causes critical addiction and inhibition of respiration which are included in the side effects of morphine is the .mu. receptors. It was thus suggested by this study that for synthesizing an ideal analgesic free from addiction and inhibition respiration, compounds which have high selectivity to .mu. receptors should be avoided and compounds which have high selectivity to .kappa. or .delta. receptors should be sought. Thus, an antagonist having high selectivity to a particular subtype of opioid receptors is necessary not only for the studies of action mechanism of analgesics but also for the development of an ideal analgesic.
It was recently found that opioid receptors concern immune system. More particularly, it was found that the agonists represented by morphine, which act on .mu. receptors exhibit immunosuppressive effect and agonists represented by enkephalin, which act on .delta. receptors exhibit immunostimulating effect (Plotnikoff, Enkephalins and Endorphins, stress and immune system, Plenum Press, 1986).
Although a number of reports have been issued concerning the immunosuppressive effects of agonists of .mu. receptors, which are represented by morphine, since the agonists of .mu. receptors exhibit critical side effects such as addiction and inhibition of respiration, it is difficult to develop an immunosuppressive agent by employing an agonist of a .mu. receptor.